1. Field of the Invention
This invention is in the field of organic chemistry. More particularly, it relates to a process for the synthesis of oxygen-containing heterocyclic organic compounds, materials formed by this process, and intermediates generated in the process. In one application, this process is used to prepare analogs of the antimalarial agent known as qinghaosu or artemisinin.
2. Background References
In prior copending U.S. patent application Ser. No. 943,555, there is disclosed a multi-step stereospecific synthesis of the oxygen-containing tetracycle artemisinin and a group of its analogs.
We have now found a new process for producing such materials. This new process is characterized by being a more direct route and by achieving the desired analogs in several fewer steps. It is also characterized by improved versatility which permits the synthesis of a wider range of possible analogs.
The present process employs ozonolysis of vinylsilanes to introduce oxygen functionality. A reference of which we are aware which involves ozonolysis of a vinylsilane is that of George Buchi et al., Journal of the American Chemical Society, Vol 100, 294 (1978). This reference illustrates the use of this reaction but effects different rearrangements and arrives at different ring structures than called for herein.
In another aspect, this invention employs unsaturated bicyclic ketones as reactants. References relating to such materials and to methods for forming some of them include W. Clark Still, Synthesis, Number 7, 453-4 (1976); Kazuo Taguchi et al., Journal of the American Chemical Society, Vol. 95, 7313-8 (1973); and E. W. Warnhoff et al., Journal of Organic Synthesis, Vol 32, 2664-69 (1967).
Other art of interest to the present invention relates to the ancient antimalarial natural product known as qinghaosu. The antimalarial qinghaosu has been used in China in the form of crude plant products since at least 168 B.C. Over the last twenty years, there has been an extensive interest in this material. This has led to an elucidation of its structure as ##STR1## The chemical name artemisinin has been applied to the material. This name will be used in this application to identify the material.
The carbons in the artemisinin structure have been numbered as set forth above. When reference is made to a particular location in a compound of this general type, it will, whenever possible, be based on the numbering system noted in this structure. For example, the carbon atoms bridged by the peroxide bridge will always be identified as the "4" and "6" carbons, irrespective of the fact that this invention can involve materials having different bridge-length structures in which these carbons would otherwise be properly numbered.
References to artemisinin and to its derivatives include the May 31, 1985 review article by Daniel L. Klayman appearing in Science, Vol 228, 1049 (1985); and the article appearing in the Chinese Medical Journal, Vol 92, No. 12, 811 (1979). Two syntheses of artemisinin have been reported in the literature by Wei-Shan Zhou, Pure and Applied Chemistry, Vol 58(5), 817 (1986); and by G. Schmid et al., Journal of the American Chemical Society, Vol 105, 624 (1983). Neither of these syntheses employs ozonolysis or the unsaturated bicyclic ketones as set forth herein.
The interest in artemisinin has prompted a desire for an effective and efficient method for its synthesis and for the synthesis of its analogs. It is also of interest to be able to apply such a method to the production of other oxygen-containing tetracycles. The prior application provided one such method. This invention provides an additional method.